Acetylcholinesterase neurotransmitter release

Acetylcholine is a neurotransmitter that functions in conveying nerve impulses across synaptic clefts within the central and autonomic nervous systems and at junctures of nerves and muscles. Following transmission of an impulse across the synapse by the release of acetylcholine, acetylcholinesterase is released into the synaptic cleft. This enzyme hydrolyzes acetylcholine to choline and acetate and transmission of the nerve impulse is terminated. The inhibition of acetylcholineasterase results in prolonged, uncoordinated nerve or muscle stimulation. Organophosphorus and carbamate pesticides (Chapter 5) along with some nerve gases (i.e., sarin) elicit toxicity via this mechanism. 

Acetylcholine is an important neurotransmitter, which is essential to complete the transmission of neural impulses from one neuron (fibers that convey impulses to the nerve cell) to another. Without acetylcholine, the body cannot function normally. When a message is sent from the brain for a muscle to move or some other bodily function to activate, acetylcholine is released. It then binds to the postsynaptic membrane, which starts and continues the movement or action. When it is time for the movement to stop, acetylcholinesterase is released to remove the acetylcholine from the synapse, so it can be used again. 

Acetylcholine is a neurotransmitter released at a synapse as a means for one neuron to communicate with a neighboring neuron. The enzyme acetylcholinesterase rapidly hydrolyzes the ester to produce choline, terminating the signal. 

Enzyme-Catalyzed Reactions Enzymes are highly specific catalysts for biochemical reactions, with each enzyme showing a selectivity for a single reactant, or substrate. For example, acetylcholinesterase is an enzyme that catalyzes the decomposition of the neurotransmitter acetylcholine to choline and acetic acid. Many enzyme-substrate reactions follow a simple mechanism consisting of the initial formation of an enzyme-substrate complex, ES, which subsequently decomposes to form product, releasing the enzyme to react again. 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

The postsynaptic membrane opposite release sites is also highly specialized, consisting of folds of plasma membrane containing a high density of nicotinic ACh receptors (nAChRs). Basal lamina matrix proteins are important for the formation and maintenance of the NMJ and are concentrated in the cleft. Acetylcholinesterase (AChE), an enzyme that hydrolyzes ACh to acetate and choline to inactivate the neurotransmitter, is associated with the basal lamina (see Ch. 11). 

We noted above that too much acetylcholine in the synapse or at a neuromuscular junction can be a problem black widow spider venom works that way by causing massive release of this neurotransmitter. There is another way to accomplish the same thing inhibit the normal route by which acetylcholine once released is subsequently removed. That route is degradation by acetylcholinesterase, an enzyme that catalyzes... 

Figure 14.9 Axonal transport of enzymes, neurotransmitter synthesis, storage in vesicles, release and uptake by presynaptic neurone or enzymic degradation. The neurotransmitter in the synaptic cleft may be removed by the presynaptic neurone (i.e. recycling), by the postsynaptic neurone or by glial cells (not shown). Alternatively, the neurotransmitter may be degraded, and therefore inactivated, by enzyme action. For example, acetylcholine is degraded by acetylcholinesterase in the synaptic cleft (Chapter 3). One of the products, choline, is transported back into the neurone to be reacted with acetyl-CoA to re-form acetylcholine. The vesicle, once empty, may also be recycled for re-packaging (Figure 14.8).

Cholinesterases, e.g., acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholi-nesterase (BChE, EC 3.1.1.8), are serine hydrolases that break down the neurotransmitter acetylcholine and other choline esters [5]. In the neurotransmission processes at the neuromuscular junction, the cationic neurotransmitter acetylcholine (ACh) is released from the presynaptic nerve, diffuses across the synapse and binds to the ACh receptor in the postsynaptic nerve (Fig. 1). Acetylcholinesterase is located between the synaptic nerves and functions as the terminator of impulse transmissions by hydrolysis of acetylcholine to acetic acid and choline as shown in Scheme 4. The process is very efficient, and the hydrolysis rate is close to diffusion controlled [6, 7]. 

Acetylcholine is a neurotransmitter that relays nerve impulses across the neuromuscular Junction. Acetylcholinesterase (AcChE) rapidly breaks dovm acetylcholine, thereby loweringits concentration in the synaptic cleft and ensuring that nerve impulses are of a finite length. As shown in Fig. 17.38, a nucleophilic serine residue reacts with the substrate to form an acetyl-serine intermediate (100) with concomitant release of choline. This intermediate is then rapidly hydrolyzed by wa-... 

A group of esterases hydrolyze simple oxygen esters. Some of fhese are designed to hydrolyze a particular ester or small group of esters, while others have a more nonspecific action. Acetylcholinesterase " " is specific for acetylcholine (Eq. 12-25), a neurotransmitter that is released at many nerve synapses and neuromuscular junctions (Chapter 30). The acetylcholine, which is very toxic in excess, must be destroyed rapidly to prepare the synapse for transmission of anofher impulse ... 

In normal transmission of a nervous impulse from nerve to nerve, acetylcholine is released into the synapse in order to excite the receiving neuron (Figure 5.10). Unless acetylcholine is rapidly broken down, the receiving nerve is constantly fired, resulting in uncoordinated muscle movement, nausea, dizziness, and eventually seizures and unconsciousness. The serine enzyme acetylcholinesterase is responsible for the expedient breakdown of the neurotransmitter acetylcholinesterase. 

Discovery. The majority of both old and new antidepressants act by virtue of their ability to inhibit monoamine transporter mechanisms in the brain. The concept that neurotransmitters are inactivated by uptake of the released chemical into the nerve terminal from which it had been released or into adjacent cells is less than 40 years old. Before this it was generally assumed that the inactivation of norepinephrine and the other monoamine neurotransmitters after their release from nerves was likely to involve rapid enzymatic breakdown, akin to that seen with acetylcholinesterase. The degradation of monoamines by the enzyme monoamine oxidase vas known early on, and in the 1950s a second enzyme catechol-O-methyl transferase (COMT) vas discovered and was thought to play a key role in inactivating norepinephrine and other catecholamines. 

A specific example is inactivation of acetylcholinesterase (Table 6-1), which catalyzes hydrolysis of acetylcholine to acetate and choline. Acetylcholine is a neurotransmitter, a chemical mediator of a nerve impulse at a junction—known as a synapse—between two neurons or between a neuron and a muscle fiber. On arrival of a nerve impulse at the ending of the neuron, acetylcholine (which is stored in the vesicles of the presynaptic nerve terminal) is released. The released... 

Both organophosphates and N-methylcarbamates are inhibitors of acetylcholinesterase (EC 3.1.1.7) (AChE), an enzyme of critical importance in synaptic nerve impulse transmission. This enzyme hydrolyzes the neurotransmitter, acetylcholine, so that its concentration near the receptor on the post-synaptic membrane is below the threshold for initiating the post-synaptic nerve impulse, except when a pre-synaptic nerve impulse has caused the release of a pulse of transmitter. The reaction mechanism of AChE is a straightforward hydrolysis mediated by water molecules and not requiring any high energy cofactor input. Synapses of insects appear to contain very much higher concentrations of AChE than mammalian synapses, on the order of 100-fold more (46. 47. ... 

Acetylcholinesterase comes into play in the following way. The arrival of a nerve impulse at the end plate of the nerve axon causes an influx of Ca +. This causes the acetylchoUne-containing vesicles to migrate to the nerve cell membrane that is in contact with the muscle cell. This is called the presynaptic membrane. The vesicles fuse with the presynaptic membrane and release the neurotransmitter. The acetylcholine then diffuses across the nerve synapse (the space between the nerve and muscle cells) and binds to the acetylcholine receptor protein in the postsynaptic membrane of the muscle cell. This receptor then opens pores in the membrane through which Na and K+ ions flow into and out of the cell, respectively. This generates the nerve impulse and causes the muscle to contract. If acetylcholine remains at the neuromuscular junction, it will continue to stimulate the muscle contraction. To stop this continued stimulation, acetylcholine is hydrolyzed, and hence, destroyed by acetylcholinesterase. When this happens, choline is no longer able to bind to the acetylcholine receptor and nerve stimulation ceases. 

Acetylcholine is synthesized from choline and acetyl-CoA, by choline acetyltransferase, in the axonal terminal bulbs of nerve cells. After acetylcholine has been released from vesicles and bound to the receptors, the neurotransmitter is rapidly hydrolyzed by the enzyme acetylcholinesterase, yielding choline, which binds poorly to acetylcholine receptors. Degradation of acetylcholine restores the resting potential in the postsynaptic membrane. After it has been released from vesicles and bound to the receptors, the neurotransmitter is rapidly hydrolyzed by the enzyme acetylcholinesterase, yielding choline, which binds poorly to acetylcholine receptors. Degradation of acetylcholine restores the resting potential in the postsynaptic membrane. 

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